GENERAL STEPS: To 740 mL of dimethylformamide (DMF) was slowly added 235 mL (2.52 mol) of phosphoryl chloride (POCl3) at 0 °C and the reaction mixture was stirred at 0 °C for 0.5 hours. Subsequently, 370 g (2.10 mol) of 4-methyl-7-nitro-1H-indole (WO00/50395) solution in DMF (1110 mL) was added dropwise to the reaction system at 0 °C. The reaction mixture was gradually warmed to 60 °C and stirred at this temperature for 2 hours. Upon completion of the reaction, 292 g (4.20 mol) of DMF (1850 mL) solution of hydroxylamine hydrochloride was slowly added dropwise to the system, with the dropwise acceleration controlled to keep the internal temperature below 80 °C. After the dropwise addition was completed, the reaction mixture was continued to be stirred at 60 °C for 40 min. Subsequently, the reaction mixture was poured into 11.1 L of ice water while cooling in an ice bath and stirred overnight. The precipitated solid was collected by filtration and washed with water. The resulting solid was suspended in 11.1 L of water and the pH of the suspension was adjusted to 7 with 1 N sodium hydroxide solution, the solid was again collected by filtration and washed with water to give 412 g of 4-methyl-7-nitro-1H-indole-3-carbonitrile (Yield: 97.6%). The resulting product was confirmed to be consistent with 3-cyano-4-methyl-7-nitro-1H-indole described in WO00/50395 by HPLC analysis.HPLC conditions: mobile phase CH3CN/H2O/70% HClO4 = 500/500/1 (v/v/v), flow rate 1.0 mL/min, detection wavelength 254 nm, column YMC- Pack Pro C18 250 x 4.6 mm.
